Production of o-cresol derivatives



Patented July 17, 1951 PRODUCTION OF N Drawing. Application o-CRESOL DERIVATIVES James D. Head, Midland, Mich, assignor to The Dow Chemical Company, Midland, Mich., a corpor'ation of Delaware December 23, 1949,

Serial No. 134,837 4 Claims. (Cl. 260-623) Thisinvention relates to the production of ocresol derivatives, and, more particularly, to the dechlorination and reduction of -ch1oro-3-fiuoro saligenin diacetate to 6-fiuoro-o-cresol acetate, as Well as to the hydrolysis of the 6-flu0roo-cresol acetate to fi-fiuoro-o-cresol.

It has been known that halogens can be removed from a benzene ring by the action of hydrogen in the presence of certain catalysts. It has also been known that ester groups can be reduced by the action of hydrogen in the presence of certain catalysts. However, so far as I am aware, it has not heretofore been known to be possible to remove selectively only one of two diiferenthalogens attached to a benzene ring in the course of a hydrogenation by means of which an ester group is reduced, i. e., to remove a chloro group and leave a fluoro group attached to the ring in the course of a hydrogenation which reduces an'ester group. By the present invention it is possible to conduct a catalytic dehalogenation to remove the chloro group from 5-chloro-3- fiuorosaligenin diacetate' and to reduce the o OHZOLICH3 group thereof to -CH3 Without removing the fluoro group.

According to the invention, saligenin diacetate is dechlorinated and reduced to 6-fiuoro-ocresol acetate by the action of 2 mols of hydrogen per mol of the 5-chloro-3-fluoro saligenin diacetate. The dechlorination and reduction are accomplished at a hydrogen pressure of from about to about 50 pounds per square inch gauge and in the presence of a palladium cata-' lyst and an acceptor for the hydrogen ions formed by the dechlorination. Such an acceptor is a compound that reacts with the hydrogen ions to form a substance having an ionization constant not greater than 3 1O (i. e., a substance that forms a one normal solution having a pH higher than about 3.5). The method of the invention is limited to the dechlorination and reduction of 5-chloro-3-fluorosa1igenin diacetate. ES-fluoro-o-cresol acetate is produced by the dechlorination and reduction. The 6-fiuoroocresol acetate is a material having particular utility because it can be used as an intermediate for the production of 3-fiuorosalicylaldehyde, which is a valuable compound for use in the preparation of oxygen-carrying chelates (see J. Am. Chem. Soc. 68, page 2254).

The dechlorination and reduction are carried out in a hydrogen atmosphere. It has been found that the dechlorination and reduction proceed when the hydrogen pressure is as low as about 10 pounds per square inch gauge, but it is usually preferred that the hydrogen pressure be at least about pounds per square inch gauge.

fiuoro saligenin diacetate (e. g., until the pres- The amount of is from about (The terms per cent are used herein to refer to per cent weight, unless otherwise indicated.)

catalyst that is ordinarily used 0.1 to about 2 per cent. and parts and parts by It is usually palladium actually present.

The hydrogen ion acceptor that is used in the practice of the invention can be any material that reacts with hydrogen ions to form a substance having an ionization constant not greater than 3 10- preferably the ionization constant is not greater than about to form acetic acid, can be used as the hydrogen Similarly, any inorganic base, or any organic base can be used as the hydrogen ion acceptor. It is usually preferred that the acceptor be water-soluble and that a water solution be used. However, the reaction can be conducted in a non-aqueous organic solution that comprises a hydrogen ion acceptor. the reaction is run batchwise, and it is preferred to employ about one mol of the hydrogen ion acceptor per mol of the 5-chloro-3iluorosaligenin diacetate; this is the amount of the hydrogen ion acceptor actually required to neutralize the hydrogen produced. However, a substantial excess (e. g., from two to three times the theoreticalamount) may be employed; likewise .16 reaction proceeds with a deficiency, but only partial conversion is possible.

, After the dechlorination and reduction of the B-fluorosaligenin diacetate, the fi-fluoro-o-cresol is hydrolyzed to 6-fluoro-ocresol. The hydrolysis is accomplished in the presence of an acid or a base, preferably in the 3 presence of at least about one mol of the fi-fluoro-o-cresol acetate.

mol of a base per The following example illustrates the new process, but is not to be construed as limiting the scope of the invention.

Example In order to prepare the -chloro-3-fluorosaligenin diacetate needed as a starting material in the practice of the invention, it was found to be necessary to produce 4 chloro alpha dimethylamino-fi-fiuoro-o-cresol, and to convert this compound to the 5-chloro-3-fluorosaligenin diacetate. The 4 chloro alpha dimethylamino-G-fluoro-o-cresol was prepared according to the following procedure:

4-chloro-2-fluorophenol (1042 methyl amine (2615 grams of a 25 per cent aqueous solution) were added to a flask and the mixture was cooled to 30 C. Aqueous formaldehyde (a total of 628 grams of a 40 per cent aqueous solution) was added stepwise with stirring to this mixture. The formaldehyde was added at such a rate that the temperature of the mixture did not rise above 45 C. When the addition of formaldehyde was complete, the mixture was stirred thoroughly and was heated on a steam bath at about 80 C. for 18 hours. The liquid in the flask was then cooled and the oily prdouct which had'separated was solidified by the addiiton of a few crystals of 4-chloro-alphadimethylamino 6 fluoro o cresol. The solid product (4 chloro alpha dimethylamino 6 fluoro o cresol) which formed was broken and separated from the liquid by filtration; the filtrate was then cooled to C. and further product which precipitated was separated by filtration and added to the original precipitate. The filtrate was then concentrated to about 700 cc. and additional 4-chloro-alpha-dimethylamino-G-fluoro-ocresol was recovered by a steam distillation. The total recovery or the desired 4 chloro alpha dimethylamino 6- fluoro-o-cresol amounted to 1376 grams which corresponds to a 95 per cent yield based on the 4-chloro-2-fluorophenol charged.

The 4 chloro alpha dimethylamino 6- fluoro-o-cresol was converted to the 5 chlorograms) and di- 3-fiuorosaligenin diacetate needed as a starting ,7

material in the practice of the invention according to the following procedure:

A sample of the 4 chloro alpha dimethylamino-G-fiuoro-o-cresol produced as described in the preceding paragraph (345 grams) and acetic anhydride (800 cc.) were refluxed for 16 hours. Fractional distillation of the resulting product through an 18 inch column resulted in the isolation of 5-chloro-3-fluorosaligenin diacetate (360 grams), which corresponds to a yield of 82 per cent based upon the 4-chloro-alpha-dimethylamino-S-fluoro-o-cresol used.

In accordance with the invention, G-fiuoro-ocresol acetate and G-fiuoro-o-cresol were produced by the following procedure:

Sodium acetate (25 grams), 5-chloro-3-fluorosaligenin diacetate (52 grams) and a methanol solution of palladium on a charcoal carrier (2 grams of a catalyst comprising 5 per cent of palladium dissolved in 150 cc. of methanol) were placed in a flask and subjected to a hydrogen atmosphere at a total pressure of about 40 pounds per square inch gauge. The flask was then placed on a commercial shaker and shaken for about minutes (until a pressure drop of about 30 pounds per square inch indicated the reaction of about 0.4 mol of hydrogen). catalyst was separated from the liquid by filtration and the filtrate was concentrated by distilling volatile matter until the liquid temperature was about C. The residue after distillation of the volatile material (comprising 6-iiuoro-o-cresol acetate) was dissolved in aqueous sodium hydroxide (200 cc. of a 10 per cent solution), and the resulting mixture was refluxed until solution was complete (about 90 minutes). This solution was acidified with sulfuric acid (about 250 grams of a 20 per cent solution), and fi-fiuoro-o-cresol produced by the hydrolysis of the G-fluoro-o-cresol acetate was recovered by a steam distillation from the acidified solution. The recovery of 17 grams of this prdouct indicated a 68 per cent yield based upon the 5 chloro 3 fluorosaligenin diacetate charged. The G-fluoro-o-cresol (CwHwFO;

boiling point 158 C. to 162 C. at a total pressure of 745 mm. of mercury) is believed to be a new compound.

A second run was made by a procedure similar to that described in the preceding paragraph using ethanol as the reaction medium; the results were not materially different.

Having described the invention, I claim:

1. A method of producing G-fluoro-o-cresol that comprises (1) dechlorinating and reducing 5-chloro-3-fluorosa1igenin diacetate to 6-fiuoroo-cresol acetate by the action of two mols of hydrogen per mol of the 5-chloro-3-fiuorosaligenin diacetate in the presence of a hydrogen ion acceptor and a palladium catalyst, and (2) hydrolyzing the G-fluoro-o-cresol acetate to free G-fiuoro-o-cresol. I

2. A method of effecting selective dehalogenation and reduction that comprises subjecting 5-chloro-3-fiuorosaligenin diacetate to the action of two mols of hydrogen per mol of the 5-chloro- S-fiurosaligenin diacetate in the presence of a hydrogen ion acceptor and a palladium catalyst.

3. A method as claimed in claim 1 in which the G-fluoro-o-cresol acetate is hydrolyzed by the action of an aqueous base.

4. A method as claimed in claim 3 in which the initial hydrogen pressure is from about 40 pounds per square inch gauge to about 50 pounds per square inch gauge.

JAMES D. HEAD.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS stracted in Chemical Abstracts 31 382'. 

1. A METHOD OF PRODUCING 6-FLUORO-O-CRESOL THAT COMPRISES (1) DECHLORINATING AND REDUCING 5-CHLORO-3-FLUOROSALIGENIN DIACETATE TO 6-FLUOROO-CRESOL ACETATE BY THE ACTION OF TWO MOLS OF HYDROGEN PER MOL OF THE 5-CHLORO-3-FLUOROSALOGENIN DIACETATE IN THE PRESENCE OF A HYDROGEN ION ACCEPTOR AND A PALLADIUM CATALYST, AND (2) 6-FLUORO-O-CRESOL. 